Research for the development of methods to control age-related diseases and bone diseases

• Project/Area Number: 20K20496
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund
• Review Section: Studies on the Super-Aging Society
• Research Institution: Juntendo University (2021-2022); The University of Tokyo (2020)
• Principal Investigator: Negishi Takako 順天堂大学, 大学院医学研究科, 特任准教授 (90451905)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥25,870,000 (Direct Cost: ¥19,900,000、Indirect Cost: ¥5,970,000); Fiscal Year 2022: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000); Fiscal Year 2020: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
• Keywords: 骨代謝学 / 加齢性疾患 / 骨粗鬆症 / 破骨細胞 / 骨芽細胞 / 骨代謝 / 加齢 / 老化 / 認知疾患

Outline of Research at the Start

本研究は下記の２つの大目的を達成するための研究を計画する。
（I）認知能、記憶・学習を司る脳・神経系が骨代謝を制御するか否か？【脳・神経→骨】
（II）力学的負荷/リハビリテーションは記憶・学習能力を改善するか？【骨→脳・神経】
また（III）骨と脳・神経のリンクを司る分子実態の同定を目指す。

Outline of Final Research Achievements

Using a mouse model of Alzheimer’s disease, we found that amyloid-b deposited in bone tissue and caused bone loss, suggesting that deposition of amyloid-b in bone tissue may occur independently of its deposition in the brain and of impaired cognitive function and learning. In this mouse model, mild exercise by treadmill induced tibia fracture susceptibility resulted from gene expression changes in certain circulating cells and knee joint cells around the time of onset of behavioral abnormalities. It was suggested that a degeneration-dependent humoral factor in the brain causes bone fragility. This bone fragility was not detected in mice with spontaneous memory deficits, suggesting neuropathic amyloid-b-dependent bone fragility.

Academic Significance and Societal Importance of the Research Achievements

加齢とともに心身の活力（運動機能や認知機能等）が低下するフレイルやロコモーティブシンドローム（ロコモ）は要介護状態の前段階であり、フレイルや初期のロコモの段階で積極的に改善をめざすことができれば超高齢社会で要介護人口の増加に歯止めをかける一助となる。その意味で、リハビリや運動療法は初期の認知症やフレイルを発症した高齢者に推奨される。リハビリや運動療法が認知症にも効果があることを分子レベルで証明できれば、それを人為的な治療・薬剤開発の基盤にできる。運動器と脳・神経系の関連を担う因子を探求することは、学術的にも新たな発見につながり、社会的にも新規制御法の開発に繋がる。

Research Products

• [Journal Article] Anterior meniscus extrusion is associated with anterior tibial osteophyte width in knee osteoarthritis-The Bunkyo Health Study (2023)
  • Author(s): Adili A, Kaneko H, Aoki T, Liu L, Negishi Y, Tomura J, Wakana S, Momoeda M, Arita H, Hada S, Shiozawa J, Kubota M, Someya Y, Tamura Y, Aoki S, Watada H, Kawamori R, Negishi-Koga T, Okada Y, Ishijima M
  • Journal Title: Osteoarthritis and Cartilage Open Volume: 5
  • Peer Reviewed / Open Access
• [Journal Article] Periosteal stem cells control growth plate stem cells during postnatal skeletal growth (2022)
  • Author(s): Tsukasaki M, Komatsu N, Negishi-Koga T, Huynh NC, Muro R, Ando Y, Seki Y, Terashima A, Pluemsakunthai W, Nitta T, Nakamura T, Nakashima T, Ohba S, Akiyama H, Okamoto K, Baron R, Takayanagi H
  • Journal Title: Nat Commun Volume: 13 Issue: 1 Pages: 4166-4166
  • DOI: 10.1038/s41467-022-31592-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis. (2021)
  • Author(s): Hosonuma M, Sakai N, Furuya H, Kurotaki Y, Sato Y, Handa K, Dodo Y, Ishikawa K, Tsubokura Y, Negishi-Koga T, Tsuji M, Kasama T, Kiuchi Y, Takami M, Isozaki T.
  • Journal Title: Rheumatology Volume: 60 Pages: 408-419
  • Peer Reviewed / Open Access
• [Journal Article] 抗RANKLモノクローナル抗体がマウス脊椎固定術モデルの骨癒合に及ぼす影響 (2021)
  • Author(s): 谷 聡二, 石川 紘司, 古賀 貴子, 工藤 理史, 松岡 彰, 丸山 博史, 山村 亮, 早川 周良, 関水 壮哉, 土谷 弘樹, 辻 まゆみ, 木内 祐二, 永井 隆士, 豊根 知明, 稲垣 克記
  • Journal Title: Journal of Spine Research Volume: 12 Pages: 538-538
  • Peer Reviewed
• [Journal Article] Myelination during fracture healing in vivo in myelin protein zero (p0) transgenic medaka line (2020)
  • Author(s): Dodo Y, Chatani M, Azetsu Y, Hosonuma M, Karakawa A, Sakai N, Negishi-Koga T, Tsuji M, Inagaki K, Kiuchi Y, Takami M
  • Journal Title: Bone Volume: 133 Pages: 115225-115225
  • DOI: 10.1016/j.bone.2020.115225
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of lipid metabolism on mouse incisor dentinogenesis. (2020)
  • Author(s): Kurotaki, Y., Sakai, N., Miyazaki, T., Hosonuma, M., Sato, Y., Karakawa, A., Chatani, M., Myers, M., Suzawa, T., Negishi-Koga, T., Kamijo, R., Miyazaki, A., Maruoka, Y., Takami, M.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 5102-5102
  • DOI: 10.1038/s41598-020-61978-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) on bone homeostasis in mice (2020)
  • Author(s): Kiyohara S, Sakai N, Handa K, Yamakawa T, Ishikawa K, Chatani M, Karakawa A, Azetsu Y, Munakata M, Ozeki M, Negishi-Koga T, Takami M
  • Journal Title: J Oral Biosci Volume: - Issue: 2 Pages: 131-138
  • DOI: 10.1016/j.job.2020.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Novel gene Merlot inhibits differentiation and promotes apoptosis of osteoclasts (2020)
  • Author(s): Yamakawa Tomoyuki、Okamatsu Nobuaki、Ishikawa Koji、Kiyohara Shuichi、Handa Kazuaki、Hayashi Erika、Sakai Nobuhiro、Karakawa Akiko、Chatani Masahiro、Tsuji Mayumi、Inagaki Katsunori、Kiuchi Yuji、Negishi-Koga Takako、Takami Masamichi
  • Journal Title: Bone Volume: 138 Pages: 115494-115494
  • DOI: 10.1016/j.bone.2020.115494
  • Peer Reviewed / Open Access
• [Presentation] Mouse model of uncoupled bone remodeling upon discontinuation of anti-RANKL antibody therapy (2023)
  • Author(s): Koji Ishikawa, Soji Tani, Nobuhiro Sakai, Yoshifumi Kudo, Hideyo Horiuchi, Hiromi Kimura-Suda, Masamichi Takami, Mayumi Tsuji, Katsunori Inagaki, Yuji Kiuchi, Takako Negishi-Koga
  • Organizer: The American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] インターロイキン-6による変形性膝関節症由来骨棘細胞のスフェロイド形成抑制作用 (2023)
  • Author(s): 根岸義文、 Adili Arepati、 Susana de Vega、百枝雅裕、金子晴香、Mehmet Zeynel Cilek、良永知穂、高藤和輝、大塚祐多、下田将之、根岸貴子、石島旨章、岡田保典
  • Organizer: 第55回日本結合組織学会学術集会
• [Presentation] 抗RANKL抗体治療の中断による骨代謝破綻の機序 (2021)
  • Author(s): 石川 紘司, 谷 聡二, 坂井 信裕, 高見 正道, 堀内 秀与, 木村 廣美[須田], 辻 まゆみ, 木内 祐二, 稲垣 克記, 根岸 貴子[古賀]
  • Organizer: 日本骨形態計測学会
• [Presentation] パーキンソン病モデルマウスを用いたドパミン神経と骨代謝についての解析 (2020)
  • Author(s): 飯田和章
  • Organizer: 日本骨形態計測学会
• [Presentation] 破骨細胞に高発現する未同定遺伝子の解析 (2020)
  • Author(s): 山川 智之
  • Organizer: 昭和学士会
• [Presentation] マウスを用いたパーキンソン病における骨代謝制御の解析 (2020)
  • Author(s): 飯田 和章
  • Organizer: 昭和学士会